Utilization of the calcium channel blocker nimodipine in affective disor- ders is based on several empirical and theoretical rationales. The L-type calcium channel blocker verapamil has been reported effective in the treatment of acute mania but not depression; nimodipine has a different profile of effects compared with verapamil. Nimodipine is: more lipid soluble; blocks cocaine-induced hyperactivity, sensitization, and dopa- mine overflow; blocks adenosine transporters and A1 receptors, and also has better anticonvulsant effects. Positive response to nimodipine in af- fective illness has been observed in 10/30 (33.3%) of the evaluable patients with refractory depression, including those with rapid and ultradian cycling disorder. In four instances this was confirmed in an off-on-off-on (B-A-B-A) design. In combination therapy a more complete response was achieved with the blind addition of carbamazepine (CBZ) in 2/14 patients. Since CBZ has recently been found by our group to inhibit calcium influx through the NMDA receptor, these data raise the possibility that drugs with differential effects on calcium (or other mechanisms) may be useful in combination in refractory patients. Several responders to nimodipine failed to remain well in a blind crossover to the phenylalkylamine verapamil, but did show a sustained response to isradipine, suggesting that the dihydroxypyridine L-type calcium channel blockers may be differentially more effective than other classes of blockers that have a different binding site on the L-type channel. A small series of patients with recurrent brief depression (RBD) have re- sponded well to the blind institution of nimodipine. Nimodipine highly significantly increased CSF somatostatin in 21 patients, while it tended to decrease TRH; i.e., effects opposite those of CBZ. Patients with frontal hypometabolism are more likely to respond to nimodipine, while those with hyperactivity respond to carbamazepine. Patients treated with nimodipine show significant increases in their peripheral type benzodiazepine receptors while those treated with the peripheral type benzodiazeine antagonist do not. These data suggest the importance of further exploring the clinical profile of nimodipine in refractory affective disorders and examining the role of altered calcium metabolism and increases in somatostatin in relationship to nimodipine response. The increased accumula-tion of intracellular calcium in the blood element of affectively ill patients has been reported in the literature and now by our group. It is evident in both basal and 5-HT-induced levels of intracellular calcium, an effect which, in combination with lithium, normalizes. We have also found preliminary evidence that this alteration may be occurring at the level of PKC regulation. We wish to further explore this finding for its mechanistic implications and to see if it would help predict which patients would be responsive to calcium-active therapeutic strategies such as nimodipine.